E-GEOD-74000
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA298696
TISSUE(S): Liver, Skin
DISEASE(S): Liver Failure,Normal,Hepatitis C Virus Infection,Hepatocellular Carcinoma
PROVIDER: E-GEOD-74000 | ExpressionAtlas | 2025-01-24
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-GEOD-74000-analysis-methods.tsv | Tabular | |||
| E-GEOD-74000-atlasExperimentSummary.Rdata | Rdata | |||
| E-GEOD-74000-configuration.xml | Xml | |||
| E-GEOD-74000-percentile-ranks.tsv | Tabular | |||
| E-GEOD-74000.condensed-sdrf.tsv | Tabular |
Items per page: 5 1 - 5 of 61 |
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Project description:Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples
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Project description:In this study we conducted transcriptomics analyses of: (i) liver samples from patients suffering from acetaminophen-induced acute liver failure (n=3) and from healthy livers (n=2) and (ii) hepatic cell systems exposed to acetaminophen, including their respective vehicle controls. The investigated in vitro systems are: HepaRG cells, HepG2 cells and a novel human skinpostnatal stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC). Clinical samples were obtained after surgical removal of the explant liver of patients diagnosed with ALF due to acetaminophen intoxication and treated by orthotopic liver transplantation (n=3). Samples from healthy livers were obtained from individuals deceased from brain damage (n=2).
2015-11-04 | GSE74000 | GEO
Project description:In this study we conducted transcriptomics analyses of: (i) liver samples from patients suffering from acetaminophen-induced acute liver failure (n=3) and from healthy livers (n=2) and (ii) hepatic cell systems exposed to acetaminophen, including their respective vehicle controls. The investigated in vitro systems are: HepaRG cells, HepG2 cells and a novel human skinpostnatal stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC). Clinical samples were obtained after surgical removal of the explant liver of patients diagnosed with ALF due to acetaminophen intoxication and treated by orthotopic liver transplantation (n=3). Samples from healthy livers were obtained from individuals deceased from brain damage (n=2). Different samples of hSKP, HepG2 and HepaRG were obtained from the same cell batch of each cell system. All cells were exposed for 24 hours to their corresponding sub cytotoxic concentrations (IC10): IC10(hSKP-HPC)=18mM; IC10(HepaRG)=13mM; IC10(HepG2)=2mM. Experiments were conducted in triplicate. This dataset is part of the TransQST collection.
2015-11-04 | E-GEOD-74000 | biostudies-arrayexpress
Project description:The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression profiles and infers mechanisms between several systems. In the present study, acetaminophen (APAP) was used as a model compound to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Comparison at the level of modulated biochemical pathways and biological processes rather than at that of individual genes appears preferable as it increases the overlap between various systems. Pathway analysis by T-profiler revealed similar biochemical pathways and biological processes repressed in rat and human hepatocytes in vitro, as well as in rat liver in vitro and in vivo. Repressed pathways comprised energy-consuming biochemical pathways, mitochondrial function, and oxidoreductase activity. Conclusion: the present study is the first that used a toxicogenomics-based parallelogram approach, extrapolating in vitro to in vivo and interspecies, to reveal relevant mechanisms indicative of APAP-induced liver toxicity in humans in vivo. Gene expression profiles of sandwich-cutlured primary rat hepatocytes exposed to 5 mM and 10 mM acetaminophen were used in a parallelogram approach in order to compare gene expression responses between rat and human using in vitro cellular models, heaptocytes, and between rat in vitro and in vivo Keywords: Toxicogenomics, dose response
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Project description:The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression profiles and infers mechanisms between several systems. In the present study, acetaminophen (APAP) was used as a model compound to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Comparison at the level of modulated biochemical pathways and biological processes rather than at that of individual genes appears preferable as it increases the overlap between various systems. Pathway analysis by T-profiler revealed similar biochemical pathways and biological processes repressed in rat and human hepatocytes in vitro, as well as in rat liver in vitro and in vivo. Repressed pathways comprised energy-consuming biochemical pathways, mitochondrial function, and oxidoreductase activity. Conclusion: the present study is the first that used a toxicogenomics-based parallelogram approach, extrapolating in vitro to in vivo and interspecies, to reveal relevant mechanisms indicative of APAP-induced liver toxicity in humans in vivo. expression profiles of sandwich-cultured primary human hepatocytes exposed to 5 mM and 10 mM acetaminophen were used in a parallelogram approach in order to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Keywords: Toxicogenomics, dose response
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2022-05-26 | PXD033550 | Pride
Project description:The goal of this project was to determine gene expression changes in the liver at different times post treatment with the common freshwater cyanobacterial toxin, cylindrospermopsin (CYN). The liver is generally considered to be the primary target of this toxin and all the data has been derived from livers of exposed animals as well as concurrent controls. Preliminary gene expression effects have been reported (Chernoff et al., 2010) and the current data extend the time course from 1 hour post exposure to 1-day post cessation of a 5-day period dosing period. Gene expression changes were determined in the livers of pregnant mice exposed to toxic levels of the cyanobacterial toxin, cylindrospermopsin. Animals were exposed to a dose of CYN that elicited significant hepatic toxicity. This multi-day study used tissue obtained 1-day, 2-days, 4-days, and 5-days after the initiation of a 5 consecutive day dosing regimen. Toxicity data including gross observations, necropsy findings and clinical chemistry endpoints indicative of hepatic, renal and homeostasis functions were collected at the same time liver tissues for gene expression analysis were obtained. Gene expression changes were analyzed on the GeneChip® Mouse Genome 430 2.0 Array.
2016-06-24 | E-GEOD-83198 | biostudies-arrayexpress
Project description:Background & Aims: The protein tyrosine phosphatase delta (PTPRD) is suppressed in several diseases including cancers and hepatitis C virus (HCV) infection. To identify hepatic pathways responsive to PTPRD function and their role in liver disease, we analyzed liver transcriptomic and clinical data from patients and established a Ptprd-deficient liver disease mouse model. Methods: Based on liver transcriptomic data, healthy patients were classified according to PTPRD expression and gene set enrichment analysis (GSEA) was performed to identify signaling pathways associated with low PTPRD expression. We established a liver disease mouse model combining impaired PTPRD expression (Ptprd+/-) and high-fat diet to assess its impact on liver transcriptomics and hepatic metabolism. Identified pathways were validated by perturbation studies in primary human hepatocytes. The clinical relevance was validated in a cohort of patients with fatty liver disease by ranking of individuals according to hepatic PTPRD expression prior analyzing the association with metabolic disease markers. Results: In healthy individuals and Ptprd+/- mice fed with normal diet, low PTPRD levels associated with a gene expression pattern involved in glucose/lipid metabolism in the liver. During diet-induced liver disease, low hepatic PTPRD led to increased blood glucose and hepatic lipid levels in the Ptprd+/- animals. Moreover, Ptprd+/- animals exhibited a pronounced unfolded protein response, which has a potential impact on hepatic insulin signaling. Indeed, silencing of PTPRD in PHH blunted the insulin-induced AKT phosphorylation. Accordingly, obese patients with low hepatic PTPRD expression exhibit increased levels of clinical markers associated with metabolic disease. Conclusion: Our data suggests an important regulatory role of hepatic PTPRD in maintaining glucose/lipid homeostasis and how its impaired expression is associated with clinical manifestations of metabolic disease.
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Project description:Retinopathy of prematurity (ROP) is the most common cause of childhood blindness worldwide and is caused by oxygen therapy necessary to prevent mortality after premature birth. We have previously demonstrated the efficacy of systemic hypoxia inducible factor (HIF) stabilization through HIF prolyl hydroxylase inhibition (HIF PHi) in protecting retinal vasculature from oxygen toxicity in a mouse model of ROP or oxygen induced retinopathy (OIR). We definitively demonstrated that hepatic HIF-1 can be activated to confer this protection using systemic dimethyloxalylglycine (DMOG) to prevent HIF-1α degradation. In this study we compare Roxadustat, a small molecule stabilizer of HIF-1 currently in phase 3 clinical trials for increasing erythropoiesis in adult patients with chronic kidney disease, to DMOG. We demonstrate that Roxadustat induces vascular protection during hyperoxia to induce the coordinated sequential growth of retinal vasculature with a 3-fold reduction in oxygen induced capillary loss (p-=0.001). In order to define the molecular mechanism of protection, we further compared the transcriptome of both liver and retina after systemic treatment with Roxadustat or DMOG. Similar gene expression profiles were identified in liver but very different effects on transcription were found in retinal tissues because Roxadustat, in contrast to DMOG, directly targets retina, confirmed by western blot and by rescue of the hepatic HIF-1 KO, two criteria that DMOG treatment is unable to fulfill. Systems pharmacologic analysis demonstrates that Roxadustat induces typical HIF regulated genes critical to aerobic glycolysis in liver and retinal tissues whereas DMOG, acting through either secreted hepatokines or by influence of systemic DMOG, downregulates cell adhesion/extracellular matrix interaction pathways while increasing expression of histone cluster genes. Stratification of liver transcriptomes to secreted gene products again shows close consensus of hepatic genes induced by both small molecules, and includes upregulation of a plethora of angiogenic proteins such as plasminogen activator inhibitor (PAI-1), erythropoietin (EPO), and orosomucosoid 2 (ORM2). Secondary validation of these transcripts by serum ELISA confirms secretion of EPO and PAI-1 into blood from liver. These findings definitively demonstrate that HIF stabilization can prevent OIR by two pathways: direct retinal HIF stabilization and induction of aerobic glycolysis or indirect, hepatic HIF-1 stabilization and increased serum angiokines. Systems pharmacology analysis therefore explains why intermittent, low dosage of small molecule HIF stabilizers creates a profound protective phenotype, because both pathways can take advantage of cytoprotection induced by the liver and by retina synergistically. These data provide a rationale for considering low dose, intermittent systemic administration of Roxadustat, currently in phase 3 trials in adults with chronic kidney disease, to eradicate ROP in children.
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